A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

Abstract

Background Aducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer’s disease (AD) trials; however, it is controversial whether it also improved cognition, which has been suggested would require a sufficiently high cumulative dose of the antibody in the brain. Therapeutic ultrasound, in contrast, has only begun to be investigated in human AD clinical trials. We have previously shown that scanning ultrasound in combination with intravenously injected microbubbles (SUS), which temporarily and safely opens the blood-brain barrier (BBB), removes amyloid and restores cognition in APP23 mice. However, there has been no direct testing of how the effects of SUS compare to immunotherapy or whether a combination therapy is more effective. Methods In a study comprising four treatment arms, we tested the efficacy of an Aducanumab analog, Adu, both in comparison to SUS, and as a combination therapy, in APP23 mice (aged 13–22 months), using sham as a control. The active place avoidance (APA) test was used to test spatial memory, and histology and ELISA were used to measure amyloid. Brain antibody levels were also determined. Results We found that both Adu and SUS reduced the total plaque area in the hippocampus with no additive effect observed with the combination treatment (SUS + Adu). Whereas in the cortex where there was a trend towards reducing the total plaque area from either Adu or SUS, only the combination treatment yielded a statistically significant decrease in total plaque area compared to sham. Only the SUS and SUS + Adu groups included animals that had their plaque load reduced to below 1% from above 10%. There was a robust improvement in spatial memory for the SUS + Adu group only, and in this group the level of Adu, when measured 3 days post-treatment, was 5-fold higher compared to those mice that received Adu on its own. Together, these findings suggest that SUS should be considered as a treatment option for AD. Alternatively, a combination trial using Aducanumab together with ultrasound to increase brain levels of the antibody may be warranted.

Naturally Occurring Antioxidant Therapy in Alzheimer’s Disease

“…Recently, aducanumab, the only potential disease-modifying therapy, was approved by the FDA through the FDA’s accelerated approval program. Aducanumab is a human monoclonal antibody that significantly reduced the formation and increased the clearance of existing Aβ plaques in mouse models of AD [ 364 , 365 , 366 ]. However, there is controversy regarding whether the drug slows disease progression in humans, as findings from currently available clinical trial data indicate strategies that reduce amyloid levels do not significantly improve cognition [ 367 ].…”

Impact of Anti-amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer’s Disease: A Focus on Aducanumab and Lecanemab

“…Ten-month-old tgAPPPS1-21 mice (AD animal model) were treated chronically with aducanumab for 4 months of weekly dosing (10 mg/kg), which showed that aducanumab was obviously suppressed Aβ toxicity and enhanced phagocytosis and cell viability ( Bastrup et al, 2021 ). To increase the brain levels of aducanumab, treatment with aducanumab combination together with ultrasound in APP23 mice, an AD model, can restore cognition in APP23 mice due to ultrasound scan with intravenously injected microbubbles, which temporarily opens the BBB, facilitating aducanumab entry into the brain ( Leinenga et al, 2021 ). In Tg2576 mice, as an AD model, aducanumab lowered Aβ plaque in a dose-dependent manner in 9-month-old mice but not in 22-month old mice ( Kastanenka et al, 2016 ; Sevigny et al, 2016 ), indicating that aducanumab was more effective in preventing Aβ aggregation than in clearing the existing amyloid plaques ( Kastanenka et al, 2016 ).…”

A Multifaceted Approach to Optimizing AAV Delivery to the Brain for the Treatment of Neurodegenerative Diseases

“…With the recent FDA approval of aducanumab (Aduhelm) it is likely that this agent will be combined with FUS mediated BBBD in the near future (de la Torre and Gonzalez-Lima, 2021). A recent study in an AD transgenic mouse has already assessed the combination of a murine aducanumab analog and BBBD using scanning FUS (Leinenga et al, 2021). A similar approach has been utilized in patients with PD dementia (Gasca-Salas et al, 2021).…”